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Tesi etd-10062014-120959

Alterations of hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Struttura

FARMACIA

Corso di studi

CHIMICA E TECNOLOGIA FARMACEUTICHE

Commissione

relatore Caleo, Matteorelatore Prof. Demontis, Gian Carlo

Parole chiave

intellectual disability

hippocampus

neurogenesis

Data inizio appello

12/11/2014;

Consultabilità

completa

Riassunto analitico

Intellectual disability (ID) is a complex disease of the central nervous system(CNS). The genetic contribution to the etiology of ID is well established and, amongthe genetic conditions, the most frequent are the X-linked intellectual disability(XLID) forms. Among the XLID genes, Oligophrenin-1 (OPHN-1) encodes a synapticRho GTPase- activating protein that regulates neuronal morphology, proliferationand maturation. The involvement of OPHN-1 in XLID was well established by theidentification of mutations within the gene, in patients with XLID. OPHN-1 gene isexpressed in brain areas that are characterized by high synaptic plasticity: in particular,the olfactory bulb and the hippocampus. However, it is not clear how mutationsin OPHN1 result in impaired neuronal development and consequent cognitivedeficits.To address these issues, I have used a mouse model of XLID based on germlinedeletion of the OPHN1 gene (OPHN1 KO; Khelfaoui et al., J Neurosci 2007). In particular,as adult hippocampal neurogenesis recapitulates the processes of neuronaldifferentiation, I have studied the development of newborn cells in the hippocampusof wt and OPHN1 KO mice. Using labelling of newborn cells with the thymidine analoguebromo-deoxy-uridine (BrdU), I found that cell proliferation in the subgranularzone of the hippocampus was not impacted by OPHN1 deficiency. Importantly, reducednumbers of BrdU-positive neurons were found 50 days after BrdU pulse labellingin OPHN1 KO mice, indicating impaired neuronal differentiation. In keepingwith these data, the number of migrating neuroblasts (stained with a doublecortin –Dcx -antibody) was also decreased in the dentate gyrus of KO animals. We alsofound reduced numbers of cells double positive for Dcx and the neuronal markerNeuN, confirming the impaired integration of newborn neurons in the hippocampusof OPHN1 KO mice.!Prompted by these results, we tested a novel therapeutic strategy based on inhibitionof the RhoA pathway, whose activity is potently stimulated by loss of OPHN-1.In particular, we administered via the drinking water fasudil, an inhibitor of theROCK kinase. Preliminary data indicate that fasudil treatment restores normalnumbers of Dcx-NeuN double positive cells in the hippocampus of OPHN1 KOanimals. !Altogether, these data demonstrate robust alterations in hippocampal neurogenesisin OPHN1 mice, and suggest a possible strategy for counteracting defects in neuronaldifferentiation triggered by loss of OPHN1.